Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2009

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dc.description.abstract

Epidemiological trends suggest that obesity is becoming a major public health
problem. Although obesity contributes toward cardiovascular risk by promoting the
development of hypertension, dyslipidaemia and diabetes mellitus (conventional risk
factors), there is increasing evidence to suggest that excess adiposity may increase risk
through effects on cardiovascular target organs that are independent of conventional risk
factors. These obesity-induced effects may be produced by mediating damage and
dysfunction of large vessels and the heart, and by promoting the development of cardiac
hypertrophy. However, the independent effect of excess adiposity on large vessels has not
been confirmed in all studies. Moreover, whether the impact of excess adiposity on cardiac
hypertrophy or cardiac damage and dysfunction is dependent on an interaction with blood
pressure (BP) is uncertain. In the present thesis I addressed these questions.
Before evaluating these questions I first identified the preferred clinical index of
adiposity when predicting BP. In this regard, some, but not all studies support the notion that
indexes of central adiposity (waist circumference or waist-to-hip ratio) are the preferred
predictors of conventional BP over indexes of general (body mass index) or subcutaneous
(skin-fold thickness) adiposity. Moreover, to my knowledge no study has been conducted in
a large study sample to evaluate whether indexes of central adiposity are the preferred
predictors of ambulatory BP, a measure of BP that is more closely associated with
cardiovascular events than conventional BP. In the first study conducted in a relatively large,
randomly selected population sample (n=300) with a high prevalence of excess adiposity
(65%), I demonstrated that waist circumference is the only clinical index of adiposity that is
associated with an increased conventional and ambulatory systolic and diastolic BP,
independent of other indexes of adiposity. With regards to the effects of excess adiposity on large arteries, there is
inconsistency in the reports demonstrating relations between indexes of adiposity and large
artery dysfunction (arterial stiffness) independent of factors such as BP, heart rate and
diabetes mellitus. As convincing independent relations between clinical indexes of adiposity
and arterial stiffness have been noted in older, but not in younger populations, I
hypothesized that age may determine whether excess adiposity promotes increases in
arterial stiffness independent of confounders. Indeed, in 508 randomly selected persons
from a population sample with a high prevalence of excess adiposity (~63% overweight or
obese), I was able to show that age markedly influenced the independent relationship
between indexes of central adiposity and an index of large artery stiffness in women but not
in men after adjusting for confounders. The adjusted effect of indexes of central obesity on
arterial stiffness was ~5-fold higher in older than in younger women.
With respect to the impact of excess adiposity on cardiac growth, although severe
obesity is associated with an enhanced impact of BP on left ventricular mass (LVM), there is
uncertainty as to whether the same effects occur in milder forms of excess adiposity, data
confounded by the high prevalence of participants receiving antihypertensive therapy in
previous studies. In the present thesis I demonstrated in a randomly recruited population
sample of 398 participants with a high prevalence of mild-to-moderate obesity and
hypertension (~41%), but in whom antihypertensive use was limited (~17%), that adiposity is
indeed associated with an enhanced impact of conventional and ambulatory BP or arterial
stiffness on LVM index and wall thickness independent of additional conventional risk
factors.
With regards to the impact of obesity on cardiac function, although obesity is a risk
factor for heart failure independent of other conventional cardiovascular risk factors, whether
this effect occurs through changes in cardiac systolic chamber function is uncertain. In the
present thesis I provide the first evidence to show in an animal model of genetic
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hypertension and dietary-induced obesity, that dietary-induced obesity promotes the
progression from compensated cardiac hypertrophy to cardiac pump dysfunction without
promoting hyperglycaemia. This effect was attributed to alterations in both intrinsic
myocardial systolic dysfunction and cardiac dilatation, effects that were associated with
excessive cardiomyocyte apoptosis and activation of enzymes that promote myocardial
collagen degradation.
Therefore in the present thesis I provide evidence to support the notion that waist
circumference should hypertension and dietary-induced obesity, that dietary-induced obesity promotes the
progression from compensated cardiac hypertrophy to cardiac pump dysfunction without
promoting hyperglycaemia. This effect was attributed to alterations in both intrinsic
myocardial systolic dysfunction and cardiac dilatation, effects that were associated with
excessive cardiomyocyte apoptosis and activation of enzymes that promote myocardial
collagen degradation.
Therefore in the present thesis I provide evidence to support the notion that waist
circumference should be measured when predicting BP changes, that excess adiposity does
indeed decrease large vessel function independent of conventional risk factors, but that this
effect is age-dependent, and that the deleterious effects of excess adiposity on cardiac
hypertrophy and cardiac pump function are indeed dependent on an interaction with BP, but
not other confounders.